Addition of low-dose fluvoxamine to low-dose clozapine monotherapy in schizophrenia: Drug monitoring and tolerability data from a prospective clinical trial

Combining fluvoxamine and clozapine may be a strategy to improve therapeuti c effects on negative symptoms in schizophrenic patients. Fluvoxamine, howe ver, markedly inhibits the metabolism of clozapine, and hazardous side effe cts may result. This study prospectively investigated the safety and tolera bility of an add-on therapy with fluvoxamine to a clozapine monotherapy in schizophrenic patients. Sixteen schizophrenic patients received 50 mg fluvo xamine as a comedication after having reached steady-state conditions under clozapine monotherapy. Patients were monitored for subjective adverse even ts, laboratory parameters, EEC and ECG recordings, orthostatic hypotension and their psychopathology. Concomitantly, serum concentrations of clozapine and metabolites were measured during monotherapy and after addition of flu voxamine. In all patients, the serum concentrations of clozapine and metabo lites were markedly increased (average: 2-3 fold, up to 5 fold for clozapin e) after addition of fluvoxamine. Side effects remained almost unchanged in frequency and severity in spite of the pharmacokinetic interactions. ECG o r laboratory parameters and orthostatic tests were similar under monotherap y and comedication. Minimal increases of EEG abnormalities were observed, b ut they were not associated with clinical impairment. Epileptic activities were always absent. The psychopathology improved which continued after star t of the comedication. Though the addition of fluvoxamine to clozapine medi cation was well tolerated and critical side effects were absent, the combin ed treatment should be controlled by drug monitoring, as serum concentratio ns of clozapine increased to unpredictably high levels. Further studies hav e to find out if the combined treatment could be advantageous to clozapine monotherapy.